Patent GB-811845-A (GB)
Title: Hydroxy-steroids and process for their manufacture
IPC: C07J75/00
Filed: 1955-07-07
Abstract: The invention comprises D 4-pregnene-3,20-dione-18,21-diols unsubstituted in the 11-position and their functional oxo or hydroxy derivatives thereof, and the 20 --> 18-lactone of D 4 - 3 - keto - 18 - hydroxyetiocholenic acid, and a process for the preparation of 18-hydroxylated steroids wherein D 4-pregnene-3,20-dione-21-ols or functional oxo or hydroxy derivatives thereof are incubated aerobically with any supravenal gland preparation or extract thereof obtained according to a method known per se, and, if desired, the 18-hydroxylated-steroids may be oxidized to 20 --> 18 lactones of the corresponding 18-hydroxy-etiocholenic acids.  The D 4 - pregnene - 3,20 - dione - 21 - ol reactants may have hydroxy groups in the 11- or 17-position, oxido groups or halogen atoms.  They may also contain further double bonds, for example, in one or more of the 1-, 5-, 6-, 7-, 9-, 11-, 14-, 15- and 16-positions.  Functional oxo or hydroxy derivatives of these reactants are, for example, esters, ethers, thioethers, thiol- or thion-esters, acetals, mercaptals, ketals and enol derivatives such as enol esters or enamines, hydrazones or carbazones.  The corresponding racemates may also be used.  Steroid reactants specified are D 4 - 3,20 - dioxo - 21 - hydroxypregnene, D 4 - 3,20 - dioxo - 11,21 - dihydroxypregnene, D 4 - 3,11,20 - trioxo - 21 - hydroxypregnene, D 4 - 3,20 - dioxo - 17a ,21 - dihydroxy - pregnene, D 4 - 3,20 - dioxo - 11,17a ,21-trihydroxypregnene, D 4-3,11,20 - triono - 17a , 21 - dihydroxy - pregnene, D 4 - 3,20 - dioxo-11b ,21 - dihydroxy - 9a  - halogen - pregnene, D 1,4 - 3,20 - dioxo - 21 - hydroxy - pregnadiene, D 1,4 - 3,20 - dioxo - 11,21 - dihydroxy - pregnadiene, D 1,4 - 3,20 - dioxo -, 11,17,21 - trihydroxy-pregnadiene, and the functional oxo or hydroxy derivatives of these compounds. The total-homogenates obtained from supravenal glands and also individual fractions have an 18-hydroxylating action. It is of advantage to use enriched preparations which are contained in the supernatant solution obtained by centrifuging the homogenates. The 18-hydroxy-steroid products may be converted into functional derivatives, for example, esters, ethers, enol-esters, enol-ethers, ketals, thioethers or thioketals, and also hydrazones, oximes or enamines.  In these compounds the hydroxy and/or oxo groups may be completely or partially functionally converted.  In the ester and enol-ester derivatives, the acid residues may be those of any desired organic carboxylic acid such as aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic, thion-carboxylic, thiol-carboxylic or sulphonic acid such as formic, acetic, chloracetic, trifluoracetic, propionic, butyric, valeric, trimethylacetic, diethylacetic, caproic, oenanthic, caprylic, palmitic, crotonic, undecanic, undecylenic, oxalic, succinic, pimelic, maleic, lactic, carbamic, alkoxy-carboxylic, b -cyclopentyl-propionic, hexahydrobenzoic, benzoic, phenyl-acetic, cyclohexyl-acetic, phenylpropionic, trimethylgallic, phthalic, furan-2-carboxylic and isonicotinic acid.  The oxidation of the 18-hydroxy-steroid products to the 20 --> 18 lactones may be carried out with periodic acid. Functionally converted hydroxy or oxo groups in the steroid products may be converted into free groups and, in the case of partial conversion, mixed esters, ethers or ether-esters may be prepared.  In the examples: D 4-3,20-diketo - 18,21 - dihydroxy - pregnene is prepared from D 4-3,20-diketo-21-hydroxy-pregnene and is then oxidized to the 20 --> 18-lactone of D 4 - 3 - keto - 18 - hydroxy - etiocholenic acid.  The D 4-3,20-diketo-18,21-dihydroxy-pregnene can be esterified with any desired organic or inorganic acid such as aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic acid, thiocarboxylic acid, thiol-carboxylic acid or sulphonic acid-particularly acetic, propionic, trimethyl-acetic, oenanthic, undecylenic, b -cyclopentylpropionic, phenyl-propionic or furan-2-carboxylic acid. Thus D 4 - 3,20 - dioxo - 18,21 - diacetoxy-pregnene is prepared using excess acetic anhydride and may be partially saponified to D 4-3,20 - dioxo - 18 - acetoxy - 21 - hydroxy - pregnene, and D 4 - 3,20 - dioxo - 18 - hydroxy - 21-acetoxy-pregnene is prepared using somewhat more than the calculated quantity of acetic anhydride and may be reacted with propionic anhydride to form D 4-3,20-dioxo-18-propionoxy-21-acetoxy-pregnene.